Neuronal and retinal tissue are high in phospholipids which contain either one or two polyunsaturated acyl chains. In our studies, we have found evidence to support a novel model for phospholipid acyl chain packing, developed in this laboratory, which involves the formation of lateral domains in the surface of the membrane. This domain formation is driven by the strong interactions of the saturated sn-1 chains relative to the weaker interactions of the polyunsaturated sn-2 chains. Differential scanning calorimetry of mixtures of a disaturated (di16:0) PC and a dipolyunsaturated (di22:6n3) PC demonstrate lateral phase separation in the gel phase. Fluorescence lifetime studies of diphenylhexatriene (DPH) in these mixed lipid systems also indicates the presence of separate domains in both the gel and liquid crystal states. This type of domain formation would create regions of the membrane rich in highly unsaturated acyl chains. Proteins located in these regions would have different functional properties than those in more saturated regions of the membrane. In addition, we have found that cholesterol preferentially interacts with saturated acyl chains and would therefore tend to concentrate in the more saturated regions of the membrane. We have also found that the effect of ethanol on metarhodopsin II formation is greater in more unsaturated lipids. The effect of domains could result in regions of the membrane which are particularly sensitive to alcohols and other membrane soluble agents. Chronic alcohol exposure is known to cause resistance to ethanol-induced membrane disordering measured in vitro, usually referred to as membrane tolerance. The potentiation of the effect of alcohols by polyunsaturated acyl chains, coupled with the observation made in this laboratory that alcohol depletes the long-chain polyunsaturated fatty acids, such as 20:4n6 and 22:6n3, may provide an explanation for the development of membrane tolerance.